8-substituted theophyllines as anti-anxiety agents

ABSTRACT

A method of alleviating anxiety in mammals exhibiting such symptoms by administering from 1 to 50 mg./kg. daily of an 8substituted theophylline.

United States Patent [7 2] Inventors Herman Hal Stein Skokie; ElizabethGoodsell, Waukegan, both of III. [21] Appl. No. 49,921 [22] Filed June25, 1970 [45] Patented Nov. 30, 1971 [7 3 1 Assignee Abbott LaboratoriesNorth Chicago, Ill.

[54] S-SUBSTITUTED THEOPHYLLINES AS ANTI- ANXIETY AGENTS 4 Claims, NoDrawings s21 u.s.c| 424/253 OTHER REFERENCES Quevauviller, ActualitisPharmacoL, 8: 106- 52 1955).

Primary ExaminerStanley .l. Freidman Attorney-Robert L. NiblackABSTRACT: A method of alleviating anxiety in mammals exhibiting suchsymptoms by administering from I to 50 mg./kg. daily of an 8-substitutedtheophylline.

S-SUBSTITUTED TI-IEOPHYLLINES AS ANTI-ANXIETY AGENTS DETAILEDDESCRIPTION OF THE INVENTION This invention relates to a method ofrelieving anxiety in patients in order to restore such patients to amore normal and thus contribute to their physical and mental well being.

Patients suffering from depression manifest one or more of a variety ofsymptoms. Generally speaking, depressed patients feel incapable ofdealing with their responsibilities; they lose interest in their jobs,families and hobbies. The predominant symptoms of depression arehypochondria, anorexia, insomnia, anergia, anhedonia and pessimism.However, some patients suffering from depression are also anxious andnervous. In treating such patients, it is desirable to have atherapeutic agent which has tranquilizing or sedative overtones. Thepresent invention provides a method of treating anxious or depressedpatients employing compounds which exhibit antidepressant and sedativeproperties. Accordingly, for the purpose of this disclosure, theii-substituted theophyllines used herein shall he referred to asnntianxiety agents.

Theophyllinc and a number of its derivatives have been reported topossess activity as central nervous system stimulants and as diuretics.(Quevauviller, Actualitis Pharmacol. 8: 106-52 (I955). Wehave'unexpectedly found that certain 8- substituted theophyllinespossess activity as sedative antidepressants. Thus, the compounds aregenerally useful in treating patients who are suffering from anxiety ormanifesting other symptoms of depression.

The compounds useful in the practice of this invention are 8-substitutedtheophyllines represented by the formula wherein R is C C alkyl or C -Ccycloalkyl.

The term alkyl, as used herein, refers to both straight and branchedchain alkyl such as methyl, ethyl, n-propyl, isopropyl, nbutyl,sec-butyl, n-pentyl, n-hexyl, n-heptyl and the like.

The antidepressant activity of the above compounds was established usingthe modified DOPA test described by Everett et al., Fed. Proc., 23,198(1964).

In the practice of this invention, the compounds are administered topatients exhibiting the symptoms of depression, including anxiety,particularly in patients in need of sedation, in dosages of from 1 to 50mg./kg. of body weight daily, either in single or divided doses. Whilethe compounds exhibit both oral and parenteral activity, the preferredroute of administration is the oral route.

The compounds of the present invention for use as antidepressant orantianxiety agents can be incorporated in to various pharmaceuticallyacceptable dosage forms such as tablets, capsules, pills, suspensionsand the like, for immediate or sustained release, by combining them withsuitable carriers or diluents according to methods well known in theart. In addition to active agent and the carrier or diluent, the dosageforms may include various excipients, binders, fillers, flavoring andsweetening agents, and the like, necessary in the formulation of thedesired pharmaceutical preparation. However, in the case of filledcapsules, for example, the antianxiety agent can be the sole ingredient.

Illustrative compounds useful in the practice of this invention are:

B-n-Pentyl-theophylline S-Cyclopentyl-theophylline8-n-Hexyl-theophylline 8 n-Butyl-theophylline 8-iso-Butyl-theophyllinell-Cyclopropyl-theophyllinc 8-n-Heptyl-theophylline The B-substitutedtheophyllines employed in the practice of 5 this invention were preparedaccording to the methods described by Hager et al., J.Am. Pharm. Assoc.,43, I52 (I954) and by first et al., J. Chem Ber., 93, 99 (I960).Generally speaking, the active agents can be prepared by reacting5,6-diamino-l,B-dimethyluracil (commercially available from AldrichChemical Company, Milwaukee, Wis.)

O l with an acid of the formula wherein R is C C, alkyl or C -Ccycloalkyl. The synthesis is represented by the following reactionsequence.

HgC-N N A The following example further illustrates the presentinvention.

EXAMPLE 1 marked activity. The results are summarized in table I.

TABLE I Compound Dosage (mg/kg.) Modified DOPA Test Response Elavil 302+ il-n-Propyl theophylline 30 3+ B-Cyclopropyl theophylline 30 4+8-Cyclopentyl theophylline 30 3+ wherein R is C C, alkyl, or C -Ccycloalkyl. cyciogr opyl theophylline. 2. The method of claim 1 whereinthe compound is 8-n- 4. The method of claim 1 wherein the compound is 8-propyl theophylline. cxciopentyl theophylline.

3. The method of claim 1 wherein the compound is 8-

2. The method of claim 1 wherein the compound is 8-n-propyltheophylline.
 3. The method of claim 1 wherein the compound is8-cyclopropyl theophylline.
 4. The method of claim 1 wherein thecompound is 8-cyclopentyl theophylline.